The extracellular matrix (ECM) and its interaction with surrounding cells offers an exciting, largely unexplored area in prostate cancer biology. One pivotal ECM protein, laminin-5, has been shown to have altered expression in various tumors. We have demonstrated a loss of laminin-5 protein expression in prostate carcinoma but the mechanism underlying this loss is not completely understood. Our hypothesis is: The loss of laminin-5 expression in prostate epithelial cells is an essential event in tumor progression. We have proposed the following three specific aims to test this hypothesis. Aim 1. Determine whether the in vitro restoration of the laminin-5 beta-3 chain in LNCaP prostate carcinoma cells will restore hemidesmosome formation, integrin binding, and subsequent signal transduction. Aim 2. Determine whether the in vitro abrogation of the laminin-5 beta-3 chain in normal prostate epithelial cells will alter adherence, signal transduction, and cell maturation. Aim 3. Characterize the effects of the loss of the laminin-5 beta-3 chain in vivo by creating an organ-specific, tetracycline-induced, transgenic mouse model. The proposed study will clarify the mechanism of the loss of laminin-5 in prostate carcinoma. The candidate will provide new insights to the mechanism underlying this loss, under the guidance of Dr. Nagle who has made major contributions to understanding the role of laminin-5 in prostate neoplasia. In addition, the creation of a novel transgenic mouse model, under the direction of Dr. McDonald, will characterize the role of laminin-5 in normal prostate development and prostate tumorigenesis. The proposed award would provide an ideal means to extend this promising line of work and facilitate the candidate's long-term career objective to become an independent physician scientist investigating the role of ECM proteins in prostate carcinoma and determining their potential prognostic value.